Introduction: Although progress has been made toward elucidating cellular pathways related to initial cystogenesis in autosomal dominant polycystic kidney disease (ADPKD), the mechanisms that contribute to disease progression and the timing of transitions remain largely unclear. We hypothesized that the predominant kidney biological processes in Pkd1RC/RC and other ADPKD models are highly dynamic throughout the disease, providing insights into the resulting kidney phenotype and conform well to those observed in human ADPKD. Methods: Kidney volume changes by class and age were determined in a large, well-characterized cohort of individuals with ADPKD and long follow-up. Similarly, Pkd1RC/RC and wild-type (WT) mice were studied longitudinally, and their kidney volume changes and function analyzed. Kidney mRNA profiles (mRNA-sequencing [mRNA-seq]) of Pkd1RC/RC mice were investigated at early, mid, and late stages, compared with those reported in other ADPKD models and humans with ADPKD. Results: In most individuals with ADPKD, kidney volume continues to increase; however, the rate of growth differs between classes and within severe classes by age. Kidney volume and function changes in Pkd1RC/RC mice conform well to the kidney volume changes in class 1C patients during adulthood. The kidney transcriptomic profile in Pkd1RC/RC mice evolves over the course of the disease, underscoring their highly dynamic kidney phenotype, presents several commonalities with other ADPKD models, and is relevant to human ADPKD. Conclusion: Our study suggests that, in ADPKD, different therapeutic strategies might be beneficial at different disease stages and identifies target candidate pathways for biomarker discovery that could be further investigated in humans.

Autosomal dominant polycystic kidney disease has some effects on cholesterol metabolism and cardiovascular disease that are shared with other chronic kidney diseases and others that are distinctive and directly caused by disruption of polycystins. The pravastatin clinical trial by Gitomer et al. does not support treatment with statins for the only purpose of delaying disease progression. Emergence of novel lipid-lowering therapies presents new therapeutic opportunities but also risks. Recent studies suggest that cholesterol is important for traffic to and function of polycystins in primary cilia.

KEY POINTS:In a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis. Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts. Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts. BACKGROUND:Pediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity. METHODS:This observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants. RESULTS:Among 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140 ), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category. CONCLUSIONS:Comprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

INTRODUCTION:Tolvaptan, a vasopressin V2 receptor (V2R) inverse agonist, is the only treatment specifically approved for autosomal dominant polycystic kidney disease (ADPKD). In addition to inhibiting cAMP synthesis, it has other effects on V2R signaling. Our goal was to mechanistically characterize the effects of MQ232, an optimized peptide of the green mamba snake and a new V2R inverse agonist, in Pkd1RC/RC mice. METHODS:Pkd1RC/RC mice were treated with MQ232 (0.5, 2, 4, or 8 nmols/kg/hour via minipump), tolvaptan (0.2% in chow), or vehicle from four to 16 weeks of age. MRI measurements of kidney volume were used for randomization and endpoint, urine was collected at 12 and 16 weeks, and mice were sacrificed at 16 weeks for blood and tissue collections. RESULTS:MQ232 and tolvaptan equally attenuated PKD. In male mice, increasing doses of MQ232 were associated with greater reductions in kidney cAMP, aquaporin-2 expression and phosphorylation, and with higher urine outputs, but equally ameliorated PKD; there was no correlation between kidney cAMP or urine output with disease attenuation. Phosphorylated/total ratios for Src, ERK, CRAF, Akt, RPS6, and Stat3 were, in general, lower in the treated mice, but this was less or reversed with increasing MQ232 doses. Analysis of previous studies with tolvaptan showed similar dose-dependent effects. This is consistent with these compounds being dual efficacy V2R ligands with inverse agonistic activity on Gαs/cAMP and, at high doses, activating β-arrestin-dependent or -independent Src and ERK signaling. Both compounds downregulated PAPPA. MQ232 inhibited IGF1Rβ phosphorylation, whereas tolvaptan at the dose/schedule used in the study did not. CONCLUSIONS:Vasopressin binding to V2R activates many cystogenic pathways: Gαs/cAMP, β-arrestin-Src and β-arrestin-ERK, and PAPPA and IGF1R signaling. Activation of cAMP-independent signaling may limit the benefit from MQ232 and tolvaptan when administered at high doses, questioning the rationale of titrating these compounds to maximally tolerated doses to treat ADPKD. Improved understanding of V2R signaling in ADPKD will lead to better therapies.

Key PointsIn autosomal dominant polycystic kidney disease, there is a linear relationship between the log-transformed total kidney volume and eGFR.There is a predictable change in the rate of eGFR decline with reduction in kidney growth rate.This framework can be used to determine treatment effect to support accelerated approval of drugs for polycystic kidney disease.BackgroundTotal kidney volume (TKV) is accepted by the US Food and Drug Administration as a surrogate end point that is reasonably likely to predict clinical benefit in autosomal dominant polycystic kidney disease and the most commonly used response biomarker for proof-of-concept intervention trials. However, the magnitude of treatment effect on TKV that would be predictive of a meaningful improvement in a clinical outcome, such as eGFR, is unknown. Inference of this from observational studies has previously been approached by examining interindividual variance in the relationship between TKV and GFR slopes over time.MethodsWe developed a novel approach to modeling the intraindividual relationship between TKV and eGFR. Patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and Halt Progression of Polycystic Kidney Disease Study A dataset were stratified by Mayo Imaging Class (MIC). Linear mixed models were fitted to eGFR with a fixed effect of log(TKV) and random intercepts, and the average slope within each MIC was estimated.ResultsWe found that within each MIC, there is a consistent, linear relationship between log(TKV) and eGFR. The model predicts that within classes 1C-1E, for each 1% point per year reduction in TKV growth rate, the rate of eGFR decline would be reduced by 0.40-0.52 ml/min per 1.73 m2 per year.ConclusionsWe have developed a new model that provides a framework for defining the magnitude of treatment effect on TKV that would support accelerated approval of a drug for autosomal dominant polycystic kidney disease.

Key PointsIn a cohort of children, 79% of families with kidney cysts had a monogenic diagnosis.Resolved cases were more likely to have a family history of kidney cysts and unresolved cases more often had unilateral cysts.Broad genetic testing revealed genetic diversity and informed prognosis and clinical management in childhood kidney cysts.BackgroundPediatric kidney cysts may indicate an underlying genetic disorder, yet the full spectrum of causes remains incompletely defined. With advances in genetic testing enabling broader evaluation, this study assessed the diagnostic utility of comprehensive genetic testing in a broad pediatric cohort with kidney cysts and characterized the underlying etiological diversity.MethodsThis observational cohort study included patients younger than 18 years enrolled between January 2020 and June 2024 at a single tertiary center. Genetic testing used targeted multigene or custom curated exome/genome sequencing panels, with segregation analysis when available. Eligible participants had at least two cysts without family history, one cyst with positive family history, or enlarged echogenic kidneys on prenatal ultrasound; those with congenital anomalies of the kidney and urinary tract associated with cysts were excluded. Clinical presentation was categorized as symptomatic, incidental, prenatal, or family screening. Primary outcomes were diagnostic yield and distribution of pathogenic variants.ResultsAmong 109 patients (median age 7.6 years, 53% female), genetic testing identified a definitive diagnosis in 81 of 100 tested patients (81%) from 72 families (79%; 14 disorders). PKD1 variants were most common (45%), while PKD2 accounted for 7%. Other causes included HNF1B or 17q12 deletions (13%), minor autosomal dominant polycystic kidney disease genes (11%; GANAB, NEK8, IFT140), monoallelic PKHD1 (3%), and biallelic PKHD1 (8%), while syndromic ciliopathy genes accounted for 5%. A positive family history of cystic kidney disease was more common among patients with a genetic diagnosis (54% versus 11%; P = 0.008). Patients without an identified genetic diagnosis more often had unilateral cysts (26% versus 4%; P = 0.53). Diagnosis by clinical symptoms was the most genetically diverse category.ConclusionsComprehensive genetic testing in pediatric kidney cysts achieved high diagnostic yield in a selected cohort and identified diverse causes beyond major autosomal dominant polycystic kidney disease/autosomal recessive polycystic kidney disease genes, supporting early evaluation to improve diagnostic accuracy, inform prognosis, and guide management, even in the absence of family history.

KEY POINTS:In an observational cohort of mostly non-Hispanic White women, pregnancy was not associated with later-life accelerated kidney function decline. Pregnancy occurring during the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial was not associated with kidney disease progression relative to women who did not become pregnant. Prior evidence indicates that adverse pregnancy outcomes may be involved in autosomal dominant polycystic kidney disease progression; pregnant women should be closely monitored. BACKGROUND:Data are conflicting regarding whether pregnancy influences disease progression in women with autosomal dominant polycystic kidney disease (ADPKD). This study examined whether pregnancy or number of pregnancies was associated with kidney disease progression in women with ADPKD. METHODS:Women with early- (study A) and late-stage (study B) ADPKD from the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial were included to examine the association between self-reported number of pregnancies (categorical predictor: no pregnancy versus 1-2 pregnancies and ≥3 pregnancies), annual slope of eGFR, annual percent change in total kidney volume (%ΔTKV), and a composite outcome (kidney failure, 50% decline in eGFR, or death) using multivariable linear regression and Cox proportional hazard models. In addition, women who became pregnant, had full-term pregnancies, and available data during study participation ( n =13) were propensity matched (1:4) to women who were not pregnant during study participation, and a mixed model was applied to determine the association of pregnancy with eGFR slope and %ΔTKV. RESULTS:Across all analyses, 455 women with a median age of 45 (interquartile range, 38-50) years and eGFR of 69±25 ml/min per 1.73 m 2 at baseline were included. One hundred ninety-nine women had 1-2 pregnancies, and 165 women had ≥3 pregnancies. There was no association of 1-2 pregnancies or ≥3 pregnancies (versus no pregnancies) with eGFR slope ( β -estimate [95% confidence interval (CI)]; 1-2 pregnancies: 0.22 [-0.44 to 0.89]; ≥3 pregnancies: -0.46 [-1.16 to 0.25]), %ΔTKV ( β -estimate [95% CI]; 1-2 pregnancies: 0.92 [-0.34 to 2.17]; ≥3 pregnancies: 0.69 [-0.67 to 2.04]), or time to composite outcome (hazard ratio [95% CI]; 1-2 pregnancies: 1.04 [0.56 to 1.93]; ≥3 pregnancies: 1.48 [0.78 to 2.77]) in adjusted models. Moreover, there was no difference in annual eGFR slope ( β -estimate: -0.14 [95% CI, -2.72 to 2.44]) and %ΔTKV ( β -estimate: 0.04 [95% CI, -3.74 to 3.82]) in women who became pregnant matched to women who did not became pregnant during their participation in the study. CONCLUSIONS:Pregnancy was not associated with ADPKD progression among women with early- and late-stage ADPKD enrolled in the HALT-PKD trial.

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis, and was associated with features of postendocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner while preserving tolvaptan’s ADPKD-modifying efficacy. In a phase II trial with tolvaptan-treated patients with ADPKD, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate/AMPK/AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.

Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent genetic kidney disorder, is characterized by diffuse kidney cysts, hypertension, and progressive kidney function decline, often leading to kidney failure by the age of 60 years. Compared with the general population, patients with ADPKD have an increased risk for development of saccular intracranial aneurysms (IAs), which can lead to intracranial bleeding and result in significant disability and mortality. Of both modifiable and nonmodifiable risk factors, the most significant is a family history of IAs or aneurysm rupture. Other contributing factors include hypertension, cigarette smoking, age, and sex. Most IAs currently detected during screening tests are small and located in the anterior circulation. Intracranial aneurysms can be manifested with thunderclap headache, which may be indicative of subarachnoid hemorrhage. Less commonly, IAs cause symptoms related to mass effect with focal neurologic deficits. Subarachnoid hemorrhage is particularly concerning, given its high case-fatality rate, which remains around 35% despite advances in neurologic care. Therefore, control of risk factors, early detection, and treatment when indicated are important to prevent adverse outcomes. Screening for IAs in ADPKD remains controversial and can be approached either universally (screening of all ADPKD patients) or selectively (screening of high-risk patients). The preferred imaging modality is brain magnetic resonance angiography without contrast enhancement or alternatively computed tomography angiography. This review provides a practical guide for medical teams managing patients with ADPKD, detailing the characteristics of IAs and their associated symptoms. It presents an algorithm for risk assessment and screening along with recommendations for treatment and follow-up care.

Cancer is the second leading cause of death worldwide. >90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP3R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP3R-mediated Ca2+ signals with dmXeB significantly reduces cell migration and invasion in vitro and metastasis in vivo. We found that this phenomenon was independent of the bioenergetic control of IP3R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP3R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins via autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP3R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP3R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.

BACKGROUND:Total kidney and liver volumes are key image-based biomarkers to predict the severity of kidney and liver phenotype in autosomal dominant polycystic kidney disease (ADPKD). However, MRI-based advanced biomarkers like total cyst number (TCN) and cyst parenchyma surface area (CPSA) have been shown to more accurately assess cyst burden and improve the prediction of disease progression. The main aim of this study is to extend the calculation of advanced biomarkers to other imaging modalities; thus, we propose a fully automated model to segment kidney and liver cysts in CT images. METHODS:Abdominal CTs of ADPKD patients were gathered retrospectively between 2001-2018. A 3D deep-learning method using the nnU-Net architecture was trained to learn cyst edges-cores and the non-cystic kidney/liver parenchyma. Separate segmentation models were trained for kidney cysts in contrast-enhanced CTs and liver cysts in non-contrast CTs using an active learning approach. Two experienced research fellows manually generated the reference standard segmentation, which were reviewed by an expert radiologist for accuracy. RESULTS:Two-hundred CT scans from 148 patients (mean age, 51.2 ± 14.1 years; 48% male) were utilized for model training (80%) and testing (20%). In the test set, both models showed good agreement with the reference standard segmentations, similar to the agreement between two independent human readers (model vs reader: TCNkidney/liver r=0.96/0.97 and CPSAkidney r=0.98), inter-reader: TCNkidney/liver r=0.96/0.98 and CPSAkidney r=0.99). CONCLUSIONS:Our study demonstrates that automated models can segment kidney and liver cysts accurately in CT scans of patients with ADPKD.

Tuberous sclerosis complex (TSC) is a highly variable autosomal dominant disease characterized by dysregulated organ development and growth. Benign tumors, termed hamartomas, may occur across organ systems but typically involve the kidney, brain, skin, heart, and lung. The diagnosis, surveillance, and clinical management of TSC requires a multidisciplinary approach, adopted by dedicated multispecialty centers worldwide. Nephrology involvement predominantly stems from the morbidity and mortality related to the prototypical kidney lesion, angiomyolipomas, whose presence and degree confers risk of CKD, hypertension, retroperitoneal bleeding, and possibly renal cell carcinoma. Surveillance of kidney structural lesions, kidney function, and BP may enable early interventions that limit kidney-related morbidity and mortality, such as mammalian target of rapamycin inhibitor therapy. We review the epidemiology, genetics, and pathogenesis of TSC and how these inform the evaluation, diagnosis, and clinical management of TSC from the vantage point of the treating nephrologist.

Tuberous sclerosis complex (TSC) is a highly variable autosomal dominant disease characterized by dysregulated organ development and growth. Benign tumors, termed hamartomas, may occur across organ systems but typically involve the kidney, brain, skin, heart, and lung. The diagnosis, surveillance, and clinical management of TSC requires a multidisciplinary approach, adopted by dedicated multispecialty centers worldwide. Nephrology involvement predominantly stems from the morbidity and mortality related to the prototypical kidney lesion, angiomyolipomas, whose presence and degree confers risk of CKD, hypertension, retroperitoneal bleeding, and possibly renal cell carcinoma. Surveillance of kidney structural lesions, kidney function, and BP may enable early interventions that limit kidney-related morbidity and mortality, such as mammalian target of rapamycin inhibitor therapy. We review the epidemiology, genetics, and pathogenesis of TSC and how these inform the evaluation, diagnosis, and clinical management of TSC from the vantage point of the treating nephrologist.